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Lactation Biology Symposium: Circadian Clocks as Mediators of the Homeorhetic Response to Lactation

14 May 2013

Homeorhetic controls are based on time-dependent changes in metabolism to establish a new physiological state, such as pregnancy or lactation, according to researchers T.Casey and K Plaut who revealed their paper at on Circadian clocks at the Lactation Biology Symposium.

Introduction

The transition from pregnancy to lactation is the most stressful period in the life of a cow. During this transition, homeorhetic adaptations are coordinated across almost every organ and are marked by changes in hormones and metabolism to accommodate the increased energetic demands of lactation.

Recent data from our laboratory showed that changes in circadian clocks occur in multiple tissues during the transition period in rats and indicate that the circadian system coordinates changes in the physiology of the dam needed to support lactation.

Circadian rhythms coordinate the timing of physiological processes and synchronize these processes with the environment of the animal. Circadian rhythms are generated by molecular circadian clocks located in the hypothalamus (the master clock) and peripherally in every organ of the body.

The master clock receives environmental and physiological cues and, in turn, synchronizes internal physiology by coordinating endocrine rhythms and metabolism through peripheral clocks. The effect of the circadian clock on lactation may be inferred by the photoperiod effect on milk production, which is accompanied by coordinated changes in the endocrine system and metabolic capacity of the dam to respond to changes in day length.

We have shown that bovine mammary epithelial cells possess a functional clock that can be synchronized by external stimuli, and the expression of the aryl hydrocarbon receptor nuclear translocator-like gene, a positive limb of the core clock, is responsive to prolactin in bovine mammary explants.

Others showed that 7 per cent of genes expressed in breasts of lactating women had circadian patterns of expression, and we report that the diurnal variation of composition of bovine milk is associated with changes in expression of mammary core clock genes.

Together these studies indicate that the circadian system coordinates the metabolic and hormonal changes needed to initiate and sustain lactation, and we believe that the capacity of the dam to produce milk and cope with metabolic stresses in early lactation is related to her ability to set circadian rhythms during the transition period.

Figure 1.

Glucose incorporation into lipids in the mammary gland increased 6-fold from prelabor to initiation of suckling, a period of time that is less than 8 h. Abdominal number 4 mammary glands were removed from anesthetized dams at each stage: prelabor, labor, parturition, and initiation of suckling (n = 6/stage). Glucose incorporation into lipids was calculated and expressed as nanomoles of glucose used per 100 mg of tissue per 1 h of incubation.

Why Circadian Clocks?

Living organisms evolved a circadian system, internal biological clocks that generate circadian rhythms, to help their bodies adapt to the daily cycle of day and night (i.e., light and dark), which result from the rotation of the earth every 24 h.

The period of a rhythm is approximately 24 h in mammals and is the length of time from peak to peak (or trough to trough). The phase of a circadian rhythm reflects where the peak and the trough occur (e.g., the peak and trough of performance within the 24-h period). The amplitude is the difference from the peak and trough.

Both external and internal cues can cause changes in metabolic and physiological rhythms (Figure 2). Changes include phase shifts, which can result from changes in light exposure; change in amplitude, which may reflect the relative strength of the underlying pacemaker; and a change in period (Bass and Takahashi, 2010).

The function of the circadian system is to coordinate internal physiological processes and synchronize these processes with the environment of the organism to ensure that physiological processes are performed at the appropriate and optimal time of day or night (Froy, 2010).

The central circadian clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus in the brain. The SCN clock is composed of multiple, single-cell circadian oscillators, which generate coordinated circadian outputs that regulate overt rhythms in physiology and behavior (Froy, 2010). Rhythmic oscillations generated by the SCN are not exactly 24 h and therefore require regularly occurring environmental signals or Zeitgebers to prevent drifting (or free-running) out of phase (Froy, 2010).

The light-dark (LD) cycle is the most important environmental cue for entraining the central circadian clock (Reppert and Weaver, 2002). Light is perceived by the retina, and the signal is transmitted via the retinohypothalamic tract to the SCN (Reppert and Weaver, 2002).

The central clock coordinates peripheral clocks located in every organ of the body. The SCN sends signals to peripheral oscillators to coordinate and synchronize rhythms across the organism via neuronal connections or circulating humoral factors (Froy, 2010). Complete destruction of SCN neurons abolishes overall circadian rhythmicity in peripheral tissues.

The loss of rhythmicity is thought to be due to loss of synchrony among individual cells in peripheral tissues because at the individual cell level each cell oscillates, but with a different phase. Thus, the central circadian clock is often termed the master clock that synchronizes all peripheral clocks found within non-SCN cells of the organism, including other regions of the central nervous system (Froy, 2010).

Summary and Conclusions

Homeorhetic controls are based on time-dependent changes in metabolism to establish a new physiological state, such as pregnancy or lactation. Likewise the ability of cows to adapt to changes in their environment including photoperiod, heat, stress, and nutrition also require time-dependent integrative homeorhetic regulation (D. E. Bauman, Cornell University, Ithaca, NY, personal communication).

We envision that during the transition period, the circadian system is modified by environmental and physiological cues that it receives. In turn, the central clock in the SCN coordinates changes in endocrine milieu and sends signals to peripheral tissues.

These signals stimulate changes in core clock genes in peripheral tissues including mammary, liver, and adipose tissues, which, in turn, effectively change the proteome and metabolome of the dam to support lactation. Further, it is likely that the circadian system coordinates the metabolic and hormonal changes needed to initiate and sustain lactation, and the capacity of the dam to produce milk and cope with metabolic stress during lactation is related to her ability to set circadian rhythms.

Studies designed to determine the biochemical and molecular mechanisms that mediate homeorhetic changes in dairy cattle may enable development of new strategies to enhance efficiency of milk production and promote animal health and well-being.

Research focused on examining the impact of circadian clocks as a fundamental homeorhetic mechanism that resets homeostasis in response to environmental changes may prove to maximize animal performance and minimize animal health-related issues that occur, particularly in early lactation.

Disruption of circadian rhythms is known to cause metabolic disease in humans and rodent models. The responses of lactating ruminants to disruption of the circadian system are likely to be unique from rodents and humans, and findings may affect management practices on dairy farms.